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Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma
Charles S Umbaugh1,2, Marie Groth2,3,4, Cihan Erkut1,2,5
1Division of Applied Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Abstract:
The embryonic transcription factor TBXT (brachyury) drives chordoma, a spinal neoplasm without effective drug therapies. TBXT's regulatory network is poorly understood, and strategies to disrupt its activity for therapeutic purposes are lacking. We developed designed ankyrin repeat proteins that block TBXT-DNA binding (T-DARPins). In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced signs of senescence and differentiation. Transcriptomic and proteomic analyses identified gene networks involved in cell cycle regulation, embryonic cell identity, and interferon response and revealed features of regulome components, such as susceptibility to pharmacologic inhibition and the fine-tuning of TBXT downstream effectors through IGFBP3. Finally, we found high interferon signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with sensitivity to JAK2 inhibitors. These findings demonstrate the potential of DARPins for probing nuclear proteins to understand the regulatory networks of transcription factor-driven cancers, including entry points for therapies that warrant testing in patients.
Insights
Researchers developed novel T-DARPins to block the TBXT (brachyury) transcription factor, showing promise for treating chordoma. These T-DARPins reduced tumor growth and identified new therapeutic strategies for this spinal cancer.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Chordoma is a spinal neoplasm driven by the TBXT (brachyury) transcription factor.
- Effective drug therapies for chordoma are lacking, and TBXT's regulatory network is poorly understood.
Purpose of the Study:
- To develop novel therapeutic strategies targeting TBXT in chordoma.
- To investigate the regulatory network of TBXT and identify potential drug targets.
Main Methods:
- Designed ankyrin repeat proteins (T-DARPins) to inhibit TBXT-DNA binding.
- Utilized transcriptomic and proteomic analyses to understand TBXT's regulatory network.
- Assessed T-DARPins' efficacy in chordoma cells and in vivo mouse models.
Main Results:
- T-DARPins reduced chordoma cell proliferation, spheroid formation, and tumor growth in mice.
- Identified gene networks involved in cell cycle, embryonic identity, and interferon response.
- TBXT promotes interferon signaling, sensitizing chordoma to JAK2 inhibitors.
Conclusions:
- T-DARPins show therapeutic potential for chordoma by targeting TBXT.
- Understanding TBXT's regulatory network reveals new therapeutic entry points, including JAK2 inhibition.
- DARPins are a viable tool for probing nuclear proteins in transcription factor-driven cancers.
